1. Field of the Invention
This invention provides a process to obtain solid micro- or nanoparticles with a homogenous structure from a microemulsion.
According to the invention, it provides a process which allows to obtain solid micro- or nanoparticles of a homogenous structure, with a size of a particles of less than 10 μm in which the solid processed compound reveals the nature, e.g., crystalline, amorphous, polymorphic, etc. . . . , typical of the original compound. According to the invention process, sizes as small as 500 nm can be obtained. Advantageously, the invention provides a process to obtain for obtaining solid micro- or nanoparticles with an aspect ratio close to the unity (1), i.e., with a substantially spheroidal morphology.
2. Description of Related Art
There are in the state of the art different processes that refer to obtaining particles finely divided as a strategy to increase their water solubility and, therefore, the bioavailability of active molecules in physiological conditions. Some of these processes have used as a model molecule, ibuprofen to show their effectiveness in this way. Below, are some details of the work based on experiments with ibuprofen.
The article by N. Rasenack, B. W. Müller, Pharmaceutical Research, 2002, 19, 1894-1900, proposes the use of a technique called in-situ Micronization as an alternative to the conventional techniques of micronization by grinding to obtain micro- and nanoparticles of solids slightly insoluble in water such as ibuprofen. To form the particulate solid an aqueous solution is poured in a stabilizing agent over a solution of ibuprofen in an organic solvent miscible in water. In this process water acts as a non-solvent of the product causing its precipitation and producing a suspension of it. This precipitation is followed by a process of “spray drying” to eliminate the liquid from said suspension and isolating the particulate solid. This solid consists of microparticles of the active principle coated with the stabilizing agent.
In the article by M. Charoenchaitrakool, F. Deghani, N. R. Foster, Ind. Eng. Chem. Res. 2000, 39, 4794-4802 racemic ibuprofen and S-ibuprofen have been micronized by the RESS process described in U.S. Pat. No. 4,582,731. This process consists in the depressurization of a solution of a product (ibuprofen) in a supercritical fluid (CO2) through a nozzle, causing its precipitation. Microparticles of the product (1-15 μm) are obtained with an irregular geometry and with a considerable loss in crystallinity.
In the article by D. Hermsdorf, Stephan Jauer, R. Signorell, Molecular Physics, 2007, 105, 8, 951-959, racemic ibuprofen and S-ibuprofen have also been micronized using the process RESS. Particles of pure ibuprofen strongly agglomerated and coagulated which consist of primary particles of 100-500 nm with irregular shapes.
The article by P. Pathak, M. J. Meziani, T. Desai, Y.-p. Sun, J. Supercrit. Fluids, 2006, 37, 279-286 describes how to obtain suspensions in water of not-agglomerated ibuprofen particles at a nanometric scale by using the RESOLV process. This process consists in depressurizing the RESS method over an aqueous solution obtaining the stabilization of particles in the aqueous medium which can contain a surfactant. This process is described in patent applications WO9965469 and WO9714407.
However, it is often desirable to obtain solid particles finely divided with a greater control of the particle size.
Mainly, three methodologies have been developed to prepare finely divided solid particles based on the use of emulsions and CO2.
In the first methodology, the synthesis of the particles is done by an anti-solvent effect of the CO2 (“anti-solvent gas”, GAS) over an emulsion of the solute to be precipitated. This methodology has been developed by Zhang et al., and comprises two stages: In the first stage, an emulsion of water in a non-polar solvent (usually iso-octane) is prepared which contains the solute to be precipitated and a surfactant, both dissolved. The second stage consists in the precipitation of the particles when the emulsion comes into contact with the CO2. This methodology is described, e.g., J. Zhang, B. Han, X. Zhang, J. He, Z. Liu, T. Jiang, G. Yang, Chem. Eur. J. 2002, 8, 17, 3879.
The second methodology, called “supercritical fluid extraction emulsion” (SFEE), is based in the precipitation of particles from the extraction by CO2 of the non-polar solvent which is a part of the emulsion. This methodology has been developed by “Ferro Corporation” (US2004071781). In this process, the synthesis of the particles also comprises two stages. In the first one, called preparation of the emulsion, the solute to be precipitated is dissolved in a non-polar saturated solvent with water. On the other hand, the surfactant is dissolved in saturated water with the same non-polar solvent. Next, both solutions are mixed to form an emulsion. Finally, the resulting emulsion is homogenized in a homogenizer. In the second stage, the precipitation of the particles takes place. The emulsion is pulverized through a nozzle in an extraction column through which CO2 circulates in a counter-current flow. The emulsion droplets come into contact with the CO2, and it extracts the non-polar solvent from the emulsion. The particles will precipitate into fine particles suspended in the aqueous phase. Therefore, through this technology the precipitation of the particles takes place by the extracting effect of the non-polar solvent which causes the precipitation. Within this methodology, based on the extracting role of CO2, Inserm Inst Nat Sante & Rech Medicale (WO2007072106) a new process has been developed to prepare the particles. This process is based in the extraction of the organic solvent of the emulsion by the CO2, upon changing it from critical conditions to a liquid state. The particles' synthesis comprises the preparation of an emulsion, and the solidification of the discontinuous phase to form the particles. The emulsion will be made up by a compressed fluid (continuous phase), and a solvent which will contain the solute to be precipitated dissolved (discontinuous phase). The compressed fluid will extract the solvent from the discontinuous phase, upon changing from critical conditions to liquid state, therefore precipitating the particles.
The third particle precipitation methodology is based on the use of emulsions made up of water as a discontinuous medium and CO2 as the continuous medium (“water-in-CO2 emulsions”). In this methodology there can be two types of different precipitations. In the first place, there is the one developed by “Ferro Corporation” (WO2004110603) which is based in the pulverization of an emulsion made up of water and CO2 within a reactor, and a later elimination of the solvents so as to finally obtain the particles. The synthesis comprises three stages. In the first one, an emulsion is prepared. The continuous phase will be made up by compressed fluid or supercritical (CO2), and the discontinuous phase by a solution (preferably aqueous) of the solute to be precipitated and/or reacted. In a second stage, the emulsion is pulverized through a nozzle forming small droplets of emulsion. In a third stage, the compressed fluid and the organic solvent from the droplets is eliminated which leads to the precipitation of the particles. In second place is the use of emulsions made up of water as a discontinuous medium and CO2 as the continuous medium. In this case, the method of precipitation is based in the precipitation of the particles from a mixture of two emulsions water/CO2. The synthesis of the particles comprises two stages: In a first stage two emulsions are prepared. The continuous phase is made up of compressed fluid or supercritical (CO2), and the discontinuous phase by the solution (preferable aqueous) of the solute to be precipitated and/or reacted. In a second stage, the two emulsions are mixed and their components react precipitating the particles. The article by C. A. Fernandez, C. M. Wai, Small 2006, 2, 11, 1266, describes how to obtain the silver nanoparticles through this methodology.
However, in many occasions it is desirable to obtain solid micro- or nanoparticles with a high homogeneity in the size of the particle and with a greater control of it. Besides, in most existing techniques to date the nature of the initial product does not manifest in the same way in the final processed product, loosing or reducing, e.g., their crystalline nature in the final product.
Therefore, there isn't yet a technology which allows to reduce the size of the particle which allows a greater control and homogeneity of it and which at the same time allows the very own properties, e.g., crystalline, of the nature of the initial product to manifest in the solid micro- or nanoparticles obtained after processing.